Top

Published in:

01-06-2017 | Original Article

Leptin induces osteoblast differentiation of human valvular interstitial cells via the Akt and ERK pathways

Authors: Mickael Rosa, Camille Paris, Yoann Sottejeau, Delphine Corseaux, Emmanuel Robin, Madjid Tagzirt, Francis Juthier, Ramadan Jashari, Antoine Rauch, André Vincentelli, Bart Staels, Eric Van Belle, Sophie Susen, Annabelle Dupont

Published in: Acta Diabetologica | Issue 6/2017

Abstract

Aims

Calcific aortic valve disease (CAVD) affects 2–6% of the population over 65 years, and age, gender, smoking, overweight, dyslipidemia, diabetes contribute to the development of this disease. CAVD results, in part, from the osteoblast differentiation of human valvular interstitial cells (VICs). This study aims to elucidate the effects of leptin on osteoblast phenotype of VICs and the signalling pathways involved.

Methods

Patients who underwent aortic valve replacement for CAVD (n = 43) were included in this study. Patients with coronary artery disease (CAD) without CAVD (n = 129) were used as controls.

Results

Patients with CAVD had higher serum leptin concentrations than CAD patients (p = 0.002). Leptin was found in calcific aortic valves, with higher concentrations in calcified versus non-calcified zones (p = 0.01). Chronic leptin stimulation of human VICs enhanced alkaline phosphatase (ALP) activity and ALP, BMP-2 and RUNX2 expression and decreased osteopontin expression. Moreover, inhibiting Akt or ERK during leptin stimulation lowered the expression of osteoblast markers in VIC.

Conclusions

Taken together, these findings indicate that leptin plays a critical role in CAVD development by promoting osteoblast differentiation of human aortic VICs in an Akt- and ERK-dependent manner. This study highlights the role of leptin in CAVD development, and further studies are needed to determine whether reducing circulating leptin levels or blocking leptin actions on VICs is efficient to slow CAVD progression.

Available only for authorised users

Nishimura RA, Otto CM, Bonow RO et al (2014) 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 63(22):e57–185. doi:10.1016/j.jacc.2014.02.536 CrossRefPubMed

Yetkin E, Waltenberger J (2009) Molecular and cellular mechanisms of aortic stenosis. Int J Cardiol 135(1):4–13. doi:10.1016/j.ijcard.2009.03.108 CrossRefPubMed

Lindman BR, Clavel MA, Mathieu P et al (2016) Calcific aortic stenosis. Nat Rev Dis Primers 2:16006. doi:10.1038/nrdp.2016.6 CrossRefPubMedPubMedCentral

Taylor PM, Batten P, Brand NJ, Thomas PS, Yacoub MH (2003) The cardiac valve interstitial cell. Int J Biochem Cell Biol 35(2):113–118CrossRefPubMed

Liu AC, Joag VR, Gotlieb AI (2007) The emerging role of valve interstitial cell phenotypes in regulating heart valve pathobiology. Am J Pathol 171(5):1407–1418. doi:10.2353/ajpath.2007.070251 CrossRefPubMedPubMedCentral

Cloyd KL, El-Hamamsy I, Boonrungsiman S et al (2012) Characterization of porcine aortic valvular interstitial cell ‘calcified’ nodules. PLoS ONE. doi:10.1371/journal.pone.0048154 PubMedPubMedCentral

Auwerx J, Staels B (1998) Leptin. Lancet 351(9104):737–742. doi:10.1016/S0140-6736(97)06348-4 CrossRefPubMed

Elkalioubie A, Zawadzki C, Roma-Lavisse C et al (2013) Free leptin, carotid plaque phenotype and relevance to related symptomatology: insights from the OPAL-Lille carotid endarterectomy study. Int J Cardiol 168(5):4879–4881. doi:10.1016/j.ijcard.2013.07.048 CrossRefPubMed

Payne GA, Kohr MC, Tune JD (2012) Epicardial perivascular adipose tissue as a therapeutic target in obesity-related coronary artery disease. Br J Pharmacol 165(3):659–669. doi:10.1111/j.1476-5381.2011.01370.x CrossRefPubMedPubMedCentral

10.

Singh M, Bedi US, Singh PP, Arora R, Khosla S (2010) Leptin and the clinical cardiovascular risk. Int J Cardiol 140(3):266–271. doi:10.1016/j.ijcard.2009.07.019 CrossRefPubMed

11.

Zeadin M, Butcher M, Werstuck G, Khan M, Yee CK, Shaughnessy SG (2009) Effect of leptin on vascular calcification in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 29(12):2069–2075. doi:10.1161/ATVBAHA.109.195255 CrossRefPubMed

12.

Zeadin MG, Butcher MK, Shaughnessy SG, Werstuck GH (2012) Leptin promotes osteoblast differentiation and mineralization of primary cultures of vascular smooth muscle cells by inhibiting glycogen synthase kinase (GSK)-3β. Biochem Biophys Res Commun 425(4):924–930. doi:10.1016/j.bbrc.2012.08.011 CrossRefPubMed

13.

Ben-Zvi D, Savion N, Kolodgie F et al (2016) Local Application of Leptin Antagonist Attenuates Angiotensin II-Induced Ascending Aortic Aneurysm and Cardiac Remodeling. J Am Heart Assoc. doi:10.1161/JAHA.116.003474 PubMedPubMedCentral

14.

Breyne J, Juthier F, Corseaux D et al (2010) Atherosclerotic-like process in aortic stenosis: activation of the tissue factor-thrombin pathway and potential role through osteopontin alteration. Atherosclerosis 213(2):369–376. doi:10.1016/j.atherosclerosis.2010.07.047 CrossRefPubMed

15.

Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162(1):156–159. doi:10.1006/abio.1987.9999 CrossRefPubMed

16.

Revillion F, Charlier M, Lhotellier V et al (2006) Messenger RNA expression of leptin and leptin receptors and their prognostic value in 322 human primary breast cancers. Clin Cancer Res Off J Am Assoc Cancer Res 12(7 Pt 1):2088–2094. doi:10.1158/1078-0432.CCR-05-1904 CrossRef

17.

Glader CA, Birgander LS, Söderberg S et al (2003) Lipoprotein(a), Chlamydia pneumoniae, leptin and tissue plasminogen activator as risk markers for valvular aortic stenosis. Eur Heart J 24(2):198–208CrossRefPubMed

18.

Shanker J, Rao VS, Ravindran V, Dhanalakshmi B, Hebbagodi S, Kakkar V (2012) Relationship of adiponectin and leptin to coronary artery disease, classical cardiovascular risk factors and atherothrombotic biomarkers in the IARS cohort. Thromb Haemost 108(4):769–780. doi:10.1160/TH12-04-0263 CrossRefPubMed

19.

Kolasa-Trela R, Miszalski-Jamka T, Grudzień G, Wypasek E, Kostkiewicz M (2011) Adiponectin, leptin, and resistin in patients with aortic stenosis without concomitant atherosclerotic vascular disease. Pol Arch Med Wewn 121(10):352–359PubMed

20.

Shapiro NI, Khankin EV, Van Meurs M et al (2010) Leptin exacerbates sepsis-mediated morbidity and mortality. J Immunol 185(1):517–524. doi:10.4049/jimmunol.0903975 CrossRefPubMedPubMedCentral

21.

Lisko I, Tiainen K, Stenholm S et al (2013) Are body mass index, waist circumference and waist-to-hip ratio associated with leptin in 90-year-old people? Eur J Clin Nutr 67(4):420–422. doi:10.1038/ejcn.2013.39 CrossRefPubMed

22.

Muc M, Todo-Bom A, Mota-Pinto A, Vale-Pereira S, Loureiro C (2014) Leptin and resistin in overweight patients with and without asthma. Allergol Immunopathol (Madr) 42(5):415–421. doi:10.1016/j.aller.2013.03.004 CrossRef

23.

Eveborn GW, Schirmer H, Lunde P, Heggelund G, Hansen J-B, Rasmussen K (2014) Assessment of risk factors for developing incident aortic stenosis: the Tromsø Study. Eur J Epidemiol 29(8):567–575. doi:10.1007/s10654-014-9936-x CrossRefPubMed

24.

Ngo MV, Gottdiener JS, Fletcher RD, Fernicola DJ, Gersh BJ (2001) Smoking and obesity are associated with the progression of aortic stenosis. Am J Geriatr Cardiol 10(2):86–90CrossRefPubMed

25.

Katz R, Budoff MJ, Takasu J et al (2009) Relationship of metabolic syndrome with incident aortic valve calcium and aortic valve calcium progression: the Multi-Ethnic Study of Atherosclerosis (MESA). Diabetes 58(4):813–819. doi:10.2337/db08-1515 CrossRefPubMedPubMedCentral

26.

Michel JB, Thaunat O, Houard X, Meilhac O, Caligiuri G, Nicoletti A (2007) Topological determinants and consequences of adventitial responses to arterial wall injury. Arterioscler Thromb Vasc Biol 27(6):1259–1268. doi:10.1161/ATVBAHA.106.137851 CrossRefPubMed

27.

Schroeter MR, Schneiderman J, Schumann B et al (2007) Expression of the leptin receptor in different types of vascular lesions. Histochem Cell Biol 128(4):323–333. doi:10.1007/s00418-007-0319-1 CrossRefPubMed

28.

Parhami F, Tintut Y, Ballard A, Fogelman AM, Demer LL (2001) Leptin enhances the calcification of vascular cells artery wall as a target of leptin. Circ Res 88(9):954–960. doi:10.1161/hh0901.090975 CrossRefPubMed

29.

Kaden JJ, Bickelhaupt S, Grobholz R et al (2004) Expression of bone sialoprotein and bone morphogenetic protein-2 in calcific aortic stenosis. J Heart Valve Dis 13(4):560–566PubMed

30.

Gomez-Stallons MV, Wirrig-Schwendeman EE, Hassel KR, Conway SJ, Yutzey KE (2016) Bone morphogenetic protein signaling is required for aortic valve calcification. Arterioscler Thromb Vasc Biol 36(7):1398–1405. doi:10.1161/ATVBAHA.116.307526 CrossRefPubMed

31.

Xu J-C, Wu G-H, Liu H-L, Liu J-T, Yan X-J, Chen J-T (2010) The effect of leptin on the osteoinductive activity of recombinant human bone morphogenetic protein-2 in nude mice. Saudi Med J 31(6):615–621PubMed

32.

Rusanescu G, Weissleder R, Aikawa E (2008) Notch signaling in cardiovascular disease and calcification. Curr Cardiol Rev 4(3):148–156. doi:10.2174/157340308785160552 CrossRefPubMedPubMedCentral

33.

Bobryshev YV, Orekhov AN, Sobenin I, Chistiakov DA (2014) Role of bone-type tissue-nonspecific alkaline phosphatase and PHOSPO1 in vascular calcification. Curr Pharm Des 20(37):5821–5828CrossRefPubMed

34.

Cho H-J, Cho H-J, Kim H-S (2009) Osteopontin: a multifunctional protein at the crossroads of inflammation, atherosclerosis, and vascular calcification. Curr Atheroscler Rep 11(3):206–213. doi:10.1007/s11883-009-0032-8 CrossRefPubMed

35.

Speer MY, Chien Y-C, Quan M et al (2005) Smooth muscle cells deficient in osteopontin have enhanced susceptibility to calcification in vitro. Cardiovasc Res 66(2):324–333. doi:10.1016/j.cardiores.2005.01.023 CrossRefPubMed

36.

Yuan ZS, Zhou YZ, Liao XB et al (2015) Apelin attenuates the osteoblastic differentiation of aortic valve interstitial cells via the ERK and PI3-K/Akt pathways. Amino Acids. doi:10.1007/s00726-015-2020-3 PubMedCentral

37.

Choi YH, Kim Y-J, Jeong HM, Jin Y-H, Yeo C-Y, Lee KY (2014) Akt enhances Runx2 protein stability by regulating Smurf2 function during osteoblast differentiation. FEBS J 281(16):3656–3666. doi:10.1111/febs.12887 CrossRefPubMed

38.

Liu G-Y, Liang Q-H, Cui R-R et al (2013) Leptin promotes the osteoblastic differentiation of vascular smooth muscle cells from female mice by increasing RANKL expression. Endocrinology 155(2):558–567. doi:10.1210/en.2013-1298 CrossRefPubMed

39.

Chavez RJ, Haney RM, Cuadra RH et al (2012) Upregulation of thrombospondin-1 expression by leptin in vascular smooth muscle cells via JAK2- and MAPK-dependent pathways. Am J Physiol Cell Physiol 303(2):C179–C191. doi:10.1152/ajpcell.00008.2012 CrossRefPubMed

Title: Leptin induces osteoblast differentiation of human valvular interstitial cells via the Akt and ERK pathways
Authors: Mickael Rosa
Camille Paris
Yoann Sottejeau
Delphine Corseaux
Emmanuel Robin
Madjid Tagzirt
Francis Juthier
Ramadan Jashari
Antoine Rauch
André Vincentelli
Bart Staels
Eric Van Belle
Sophie Susen
Annabelle Dupont
Publication date: 01-06-2017
Publisher: Springer Milan
Published in: Acta Diabetologica / Issue 6/2017
Print ISSN: 0940-5429
Electronic ISSN: 1432-5233
DOI: https://doi.org/10.1007/s00592-017-0980-3

ACC 2024 Congress Coverage

Heart Failure Video

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Leptin induces osteoblast differentiation of human valvular interstitial cells via the Akt and ERK pathways

Abstract

Aims

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Aims

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 6/2017

Bilateral lower limb edema induced by rapid improvement of glycemic control with insulin therapy in a subject with poorly controlled type 2 diabetes

The English National Screening Programme for diabetic retinopathy 2003–2016

Cause-specific mortality in a cohort of Brazilian patients with type 1 diabetes

Glucose-independent association of adiposity and diet composition with cardiovascular risk in children and adolescents with type 1 diabetes

Fine tuning of nutritional therapy by using continuous glucose monitoring in an infant with a gastrointestinal malformation

The microRNA-7-mediated reduction in EPAC-1 contributes to vascular endothelial permeability and eNOS uncoupling in murine experimental retinopathy

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page